Loss-of-function of the protein kinase C δ (PKCδ) causes a B-cell lymphoproliferative syndrome in humans.

Defective lymphocyte apoptosis results in chronic lymphadenopathy and/or splenomegaly associated with autoimmune phenomena. The prototype for human apoptosis disorders is the autoimmune lymphoproliferative syndrome (ALPS), which is caused by mutations in the FAS apoptotic pathway. Recently, patients with an ALPS-like disease called RAS-associated autoimmune leukoproliferative disorder, in which somatic mutations in NRAS or KRAS are found, also were described. Despite this progress, many patients with ALPS-like disease remain undefined genetically. We identified a homozygous, loss-of-function mutation in PRKCD (PKCδ) in a patient who presented with chronic lymphadenopathy, splenomegaly, autoantibodies, elevated immunoglobulins and natural killer dysfunction associated with chronic, low-grade Epstein-Barr virus infection. This mutation markedly decreased protein expression and resulted in ex vivo B-cell hyperproliferation, a phenotype similar to that of the PKCδ knockout mouse. Lymph nodes showed intense follicular hyperplasia, also mirroring the mouse model. Immunophenotyping of circulating lymphocytes demonstrated expansion of CD5+CD20+ B cells. Knockdown of PKCδ in normal mononuclear cells recapitulated the B-cell hyperproliferative phenotype in vitro. Reconstitution of PKCδ in patient-derived EBV-transformed B-cell lines partially restored phorbol-12-myristate-13-acetate-induced cell death. In summary, homozygous PRKCD mutation results in B-cell hyperproliferation and defective apoptosis with consequent lymphocyte accumulation and autoantibody production in humans, and disrupts natural killer cell function.

Respiratory syncytial virus disease in preterm infants in the U.S. born at 32-35 weeks gestation not receiving immunoprophylaxis.

BACKGROUND: The Respiratory Syncytial Virus (RSV) Respiratory Events Among Preterm Infants Outcomes and Risk Tracking (REPORT) study evaluated RSV disease burden in U.S. preterm infants 32-35 weeks gestational age (wGA) not receiving RSV prophylaxis. METHODS: Preterm infants <6 months of age as of November 1st were followed prospectively at 188 clinics from September to May 2009-2010 or 2010-2011. Nasal and pharyngeal swabs were collected for medically attended acute respiratory illnesses (MAARI) and tested for RSV by qRT-polymerase chain reaction. Risk factors were assessed using multivariate Cox proportional hazard model adjusted for seasonality. RESULTS: Of 1642 evaluable infants, 287 experienced RSV MAARI. Rates of RSV-related MAARI, outpatient lower respiratory tract illness, emergency department visits and hospitalization (RSVH) during November to March were 25.4, 13.7, 5.9 and 4.9 per 100 infant-seasons, respectively. Preschool-aged, nonmultiple-birth siblings and daycare attendance were consistently associated with increased risk of RSV. RSVH rates were highest in infants 32-34 and 35 wGA who were <6 months of age during November to March with daycare attendance or nonmultiple-birth, preschool-aged siblings (8.9 and 9.3 per 100 infant-seasons, respectively, versus 3.5 for all other infants, P<0.001). Chronologic age <3 months was associated with a higher RSVH rate for infants 35 wGA but not for infants 32-34 wGA. CONCLUSIONS: In US preterm infants who were 32-35 wGA, <6 months on November 1st and not receiving RSV prophylaxis, the burden of RSV MAARI was 25 per 100 infant-seasons. The highest RSVH rates occurred among those with daycare attendance or nonmultiple-birth, preschool-aged siblings while they were <6 months of age during the RSV season.

The relationship between vaccine refusal and self-report of atopic disease in children.

BACKGROUND: In the last 3 decades, there has been an unexplained increase in the prevalence of asthma and hay fever. OBJECTIVE: We sought to determine whether there is an association between childhood vaccination and atopic diseases, and we assessed the self-reported prevalence of atopic diseases in a population that included a large number of families not vaccinating their children. METHODS: Surveys were mailed to 2964 member households of the National Vaccine Information Center, which represents people concerned about vaccine safety, to ascertain vaccination and atopic disease status. RESULTS: The data included 515 never vaccinated, 423 partially vaccinated, and 239 completely vaccinated children. In multiple regression analyses there were significant ( P < .0005) and dose-dependent negative relationships between vaccination refusal and self-reported asthma or hay fever only in children with no family history of the condition and, for asthma, in children with no exposure to antibiotics during infancy. Vaccination refusal was also significantly ( P < .005) and negatively associated with self-reported eczema and current wheeze. A sensitivity analysis indicated that substantial biases would be required to overturn the observed associations. CONCLUSION: Parents who refuse vaccinations reported less asthma and allergies in their unvaccinated children. Although this relationship was independent of measured confounders, it could be due to differences in other unmeasured lifestyle factors or systematic bias. Further research is needed to verify these results and investigate which exposures are driving the associations between vaccination refusal and allergic disease. The known benefits of vaccination currently outweigh the unproved risk of allergic disease.